The information provided herein is intended solely to assist the understanding of the reader. None of the information provided nor references cited is admitted to the prior art to the present invention. Each of the references cited herein is incorporated in its entirety.
The identification of the molecular events that underlie the development of human tumors presents a major challenge in the design of improved strategies in the prevention, management, and cure of these diseases (Barker, K. T. et al. BRK Tyrosine Kinase Expression in a High Proportion of Human Breast Carcinomas, Oncogene 1997, 15:799-805). The role of aberrantly regulated protein tyrosine kinases (PTKs) in human tumor development is the subject of intense investigation (Barker id.).
Protein kinases are regulators of cellular signaling and their functional dysregulation common in carcinogenesis and many other disease states or conditions (Mizuguchi, Y. et al., Breast Tumor Kinase/Protein Tyrosine Kinase 6 (Brk/PTK6). J Hepatology 2015, 63, 399-407; Mahmoud, K. A. et al., Discovery of 4-Anilino α-Carbolines as Novel Brk Inhibitors. Bioorganic & Medicinal Chemistry Letters 2014, 24:1948-1951: Nobel, M. E. M. Protein Kinase Inhibitors: Insights into Drug Design from Structure. Science 2004, 303:1800-1805). The human genome encodes over 500 protein kinases that share a catalytic domain conserved in sequence and structure but which are notably different in how their catalysis is regulated (Nobel id.). Protein kinases regulate key signal transduction cascades that control or are involved in the control of physiological functions including cellular growth and proliferation, cell differentiation, cellular development, cell division, stress response, transcription regulation, aberrant mitogenesis, angiogeneisis, abnormal endothelial cell-cell or cell-matrix interactions during vascular development, inflammation, Jun-N-terminal kinase (JNK) signal transduction, and several other cellular processes (see U.S. Pat. No. 8,470,818). Protein kinase inhibitors have been established as promising drugs that inhibit overactive protein kinases in cancer cells (Mahmoud id.).
A partial, non-limiting list of these kinases includes: BRK, FGR, PDGFRα(V561D), DDR2, LYNa, SRM, PDGFRα, LCK, DDR1, KDR, ACK, JAK1, LYNb, KIT, CSK, YES, KIT(V560G), BLK, MST1, JAK2, RET(S891A), SRC, FYN(isoform a), RET(G691S), FYN(isoform b), PDGFRβ, RET, FLT4, RET(Y791F), skMLCK, FRK, MST2, FLT1, AurA, FLT3, JAK3, RET(M918T), WNK3, p388, FGFR2, MNK1, MNK2, PIK3CA/PIK3R1, PDGFRα(D842V), MET, FGFR1, BRAF(V600E), MAP2K5, KIT(D816E), ALK, FGFR3, RAF1, MAP2K3, HER4, KIT(D816V), Erk5, EGFR, YES(T348I), KIT(V654A), KIT(D816Y), PDGFRα(T674I), BRAF, ABL, HER2, EPHA5, ROCK2, KIT(T670I), PKD3, MST4, MAP2K1, MAP2K2, MST3, ROCK1, IGF1R, PKD2, MAP2K6, Erk2, PKD1, MAP2K7, Erk1, MAP2K4, and BTK (see U.S. Pat. No. 8,470,818 B2 for detailed information on kinase nomenclature and biological properties). Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems.
The novel compounds of this invention inhibit the activity of one or more protein kinases and are, therefore, expected to be useful in the treatment of kinase-related diseases or conditions.